Desmopressin, also known as dDAVP, is a nonapeptide and the therapeutically active ingredient (as the acetate salt) in the pharmaceutical product Minirin®, which is marketed inter alia as a nasal spray and a tablet formulation. Desmopressin is primarily used in the treatment of primary nocturnal enuresis, i.e. bedwetting, in children, but it is approved also for the treatment of nocturia and diabetes insipidus. The first market introduction of the tablet formulation was in Sweden in 1987. The composition of the marketed tablet form of desmopressin has remained the same to date.
The tablet form of desmopressin was first disclosed as set forth in the U.S. Pat. No. 5,047,398. The subsequently issued marketing authorisations relate to a tablet where i.a. the mannitol, talc and cellulose components exemplified in U.S. Pat. No. 5,047,398 are replaced with potato starch. In addition to desmopressin acetate and potato starch, the present tablet components are lactose, polyvinylpyrrolidone (PVP) and magnesium stearate that together form a homogeneous tablet compressed from a granulate. This composition is inter alia disclosed in the publication WO 03/94886 A1 (see page 28).
Since desmopressin is a nonapeptide containing a disulfide bond, its stability must always be considered. Representative publications addressing the problem of the stability of desmopressin in pharmaceutical formulations are EP 1255557 A1, EP 752877 A1 and EP 710122 A1.
Desmopressin containing granulate has to date been prepared in a wet granulation process involving a sequence of several sieving and mixing steps performed at ambient temperature and humidity followed by drying (cf. example 1 herein). One of the objectives of that procedure is to keep shearing forces that desmopressin may be subjected to at a minimum level. The main disadvantages of said procedure is that it is rather time-consuming and labor intensive.
The publication WO 97/15297 A1 (examples 6 and 10) discloses a wet granulation method for the preparation of a buccal delivery system for desmopressin.
As a mixture of water and ethanol is used as the granulation liquid in the prior art granulate preparation, the resulting tablet inevitably contains solvent residues, typically 5–6% of water and 0.1% of ethanol (percentage by weight). Complete removal of solvent residues by drying is impractical, as conditions for complete drying of solid dosage forms tend to be either too costly in industrial scale or potentially thermally damaging to the desmopressin. The primary purpose of the added ethanol is to shorten the time of drying (via an azeotrope).
It is an objective of the present invention to overcome the aforementioned disadvantages.